Ways to obtain 2-phenyl-3-aminopyridine, or acylated derivative, or a substituted phenyl derivatives

 

(57) Abstract:

The invention relates to a method for producing 2-phenyl-3-aminopyridine or substituted phenyl derivatives, which is that the connection f-crystals (VIII) is subjected to interaction with connection f-crystals (IV) in which the substituents have the following meanings: X is Cl, Br or J; Z is H, (C1-C4)alkyl, methoxy, triptoreline, F or CL; Ar is (C6-C10)aryl; R3and R4selected from H4(C1-C6)alkyl. The process is conducted in an inert solvent in the presence of base and palladium catalyst to obtain compound f-ly (X). The invention relates also to a method for producing acylated 2-phenyl-3-aminopyridine, which is that the connection f-crystals (III) is subjected to interaction with connection f-crystals (IV) in an inert solvent in the presence of base and palladium catalyst to obtain compound f-ly (V), which can be translated in connection F.-ly (X). The compounds are antagonists of substance P and can be used in medicine. 3 S. and 12 C.p. f-crystals.

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The invention relates to a method for producing 2-phenyl-3-amine the e suitable for producing compounds which are useful as antagonists of substance P.

Substance P is a natural undecapeptide belonging to theminimum family of peptides, the members of which have a rapid stimulatory effect on smooth muscles. Substance P is a pharmaceutically active neuro-peptide that is produced in mammals, and has a characteristic amino acid sequence described in U.S. patent 4680283. In this area shows in detail the involvement of substance P and other tachykinins in the pathophysiology of numerous diseases. For example, it is shown that substance P is involved in the development of pain or migraine, as well as diseases of the Central nervous system, such as a state of fear and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, and diseases of the gastrointestinal tract, such as ulcerative colitis, symptoms of inflamed bowel and Crohn's disease. It was reported that tachykinin antagonists are useful for treating such diseases and for the treatment of cardiovascular diseases, allergic diseases, immune regulation, expansion vessels, bronchospasm, reflex or neuroregulation internal org">

Various antagonists of substance P can be obtained from 2-phenyl-3-aminopyridine. For example, in U.S. patent 5323929 described antagonists of substance P formula

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where R3is substituted or unsubstituted aryl, heteroaryl or cycloalkyl. These antagonists can be obtained by the recovery of 2-phenyl-3-aminopyridine, followed by reductive amination of the obtained 2-phenyl-3-aminopiperidine, using the appropriate aldehyde of the formula R3SNO. Alternatively, these antagonists substance P can be obtained by interaction of 2-phenyl-3-aminopyridine with the compound of the formula R3SNO or R3CH2X, where X is a leaving group, to obtain the pyridine analogue antagonist substance P. Then the pyridine analogue restore to obtain the final product.

Other antagonists of substance P, which can be obtained from 2-phenyl-3-aminopyridine, described in U.S. patent 5773450 and in WO 97/08144 and PCT/IB97/01466. Methods of obtaining antagonists of substance P using 2-phenyl-3-aminopyridine is also described in U.S. patent 5232929.

However, the conventional method used to obtain 2-phenyl-3-aminopyridine, described Miller and Farrell (Tetrahedron Letters, 1998, 39: 6441-6444) is Costituzione 2-phenyl-3-aminopyridine, it substituted phenyl derivatives and their salts. In one embodiment, the invention involves reacting the compounds of formula

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or

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with the compound of the formula

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in an inert solvent to the reaction in the presence of a base and palladium catalyst to obtain the compounds of formula

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or

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where X is C1, Br or I;

Z is H, (C1-C4)alkyl, methoxy, triptoreline, F or C1;

AG is a (C6-C10)aryl, optionally substituted by 1 to 3 groups of R5;

R1is (C1-C6normal or branched alkyl, (C3-C7)cycloalkyl or (C6-C10)aryl, the alkyl, cycloalkyl or aryl optionally substituted by 1 to 3 groups of R5;

R3and R4independently selected from H and (C1-C6)alkyl, where R3and R4are (C1-C6)alkyl, they may be condensed together with the formation of the ring structure and

each R5independently selected from halogen, cyano, nitro, (C1-C6)of halogensubstituted alkyl, (C1-C6)alkoxy, (C6-C10)aryloxy, (C1-C6)halogen-substituted alkoxy, (C1-C< -C6)alkylsulfonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkyl-OC(O)-, (C1-C6)alkyl-OC(O)-(C1-C6)alkyl, (C1-C6)alkyl-C(O)O-, (C1-C6)alkyl-C(O)-(C1-C6)alkyl-O-, (C1-C6)alkyl-C(O)-, (C1-C6)alkyl-C(O)- (C1-C6)alkyl, (C6-C10)aryl-, (C6-C10)aryl-(C1-C6)alkyl - and (C3-C7)cycloalkyl, where one or two carbon atoms of the specified cycloalkyl can be optionally replaced by nitrogen, oxygen or sulfur.

In a preferred embodiment, the compound of formula III or VIII is produced by interaction of the compounds of formula

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with the compound of the formula

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or

ArCHO VII

in an inert solvent reaction

where Y is C1, Br, I or-OC(O)R2;

and R2is a normal or branched (C1-C6)alkyl, (C3-C7)cycloalkyl or (C6-C10)aryl, and these alkyl, cycloalkyl or aryl optionally substituted by 1 to 3 groups of R5where the specified reaction of the compound III or VIII with a compound IV occurs essentially simultaneously with or after the specified reaction of compound I with soedinenii obtaining salt of compound X.

In one embodiment, the above-described method of the invention involves the following stages:

(a) interactions of the compounds of formula

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with the compound of the formula

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in an inert solvent to the reaction in the presence of a base to obtain the compounds of formula

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(b) interaction of the compounds of formula III with the compound of the formula

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in an inert solvent to the reaction in the presence of a base and palladium catalyst to obtain the compounds of formula

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(C) removing the protective group from compounds of formula V in an aqueous solution of acid to obtain the salt of the compounds of formula

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where X, Y, Z, R1, R2, R3, R4and R5have the values specified above.

In another embodiment of the method described above, the invention involves the following stages:

(a) interaction of the compounds of formula

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with the compound of the formula

ArCHO VII

in an inert solvent reaction with obtaining the compounds of formula

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(b) essentially simultaneously with, or after stage (a), the interaction of the compounds of formula VIII with the compound of the formula

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in an inert solvent to the reaction in the presence of a base and palladium catalyst to obtain the compounds of formula

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g is but

where Ar, X, Z, R3, R4and R5determined as described above.

In preferred embodiments of the invention X is Cl, Z is N, and where appropriate, Y is C1.

In a preferred embodiment, the AG is selected from phenyl and naphthyl, optionally substituted by 1 to 3 groups of R5.

In preferred embodiments of the invention R1and R2are the same and, preferably, are both stands.

In other embodiments, R1is stands and R2is tert-bootrom.

In another embodiment, R1and R2independently selected from normal or branched (C1-C6)alkyl and phenyl.

In another preferred embodiment, R3and R4are N.

In another preferred embodiment, each R5independently selected from normal or branched (C1-C6)alkyl, phenyl, benzyl, trifloromethyl, (C1-C6)alkoxy, F, Cl, triptoreline.

In an additional preferred embodiment, Z is H; R1and R2are the same, are independently a normal or branched (C1-C6)alkyl and phenyl, and optionally substituted from 1 branched (C1-C6)alkyl, phenyl, benzyl, trifloromethyl, (C1-C6)alkoxy, triptoreline.

The term "alkyl", as used here, unless otherwise specified, refers to a saturated monovalent hydrocarbon radical, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.

The term "alkenyl", used herein, unless otherwise specified, refers to a monovalent hydrocarbon radical having at least one double bond in the carbon-carbon bonds, including, but not limited to, vinyl, 1-propenyl, allyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl and including E and Z isomers such alkenyl radicals.

The term "quinil", used herein, unless otherwise specified, refers to a monovalent hydrocarbon radical having at least one triple bond carbon-carbon bonds, including, but not limited to, ethinyl, 2-PROPYNYL and 3-butynyl.

The term "aryl", as used here, unless otherwise specified, refers to an aromatic radical, including, but not limited to, phenyl, naphthyl, pyridyl, hinely, thienyl, furyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl.

The term "alkoxy", ISOE is hydroxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

The term "halogen" used herein, unless otherwise specified, refers to a radical derived from the elements fluorine, chlorine, bromine and iodine.

The term "halogen-substituted alkyl", as used here, unless otherwise specified, refers to alkyl substituted by one or more Halogens including, but not limited to, chloromethyl, deformity, trifluoromethyl and 2,2,2-trichlorethyl.

The term "halogen-substituted alkoxy", as used here, unless otherwise specified, refers to alkoxygroup substituted by one or more Halogens including, but not limited to, chloromethoxy, deformedarse, triptoreline and 2,2,2-trichloroethane.

The term "alkylthio", used herein, unless otherwise specified, refers to S-alkyl, the radical, including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric and tert-butylthio.

The term "alkylsulfonyl", used herein, unless otherwise specified, refers to-SO-alkyl, the radical, including, but not limited to, methylsulfinyl, ethylsulfinyl and isopropylphenyl.

The term "alkylsulfonyl" as used here, if not CC is sulfonyl and isopropylphenyl.

All publications, patents and patent applications mentioned in this application is entirely incorporated here by reference.

The method according to the present invention can be obtained 2-phenyl-3-aminopyridine and its substituted derivatives with a higher yield than that obtained by using conventional methods, and it is less sensitive to the air.

Getting 2-phenyl-3-aminopyridine according to the invention is illustrated by the following reaction schemes 1-3 (see below).

Stage 1 scheme 1 includes protection compounds I. In particular, compound I reacts with allermuir reagent of formula II in the presence of a base and an inert solvent to the reaction at a temperature of from -20 to 60oC for from 1 to 48 h to obtain acylated aniline compounds of formula III. Suitable bases include, but are not limited to triethylamine, diisopropylethylamine, 2,6-lutidine, N,N,N',N'-tetramethylethylenediamine, potassium carbonate, sodium hydroxide and potassium hydroxide. Suitable inert solvents for the reaction include, but are not limited to, dichloromethane, dichloroethane and toluene. For example, in one embodiment, the stage 1 scheme 1 is carried out in the presence of triethylamine and dichloro the e 1 involves the reaction of a combination of Suzuki (Miyaura et al., Chem. Rev. 1995, 95:2457) between the compound of formula III and a compound of formula IV to obtain biaryl formula V. Stage 2 is carried out in an inert solvent to the reaction in the presence of a base and a palladium catalyst at a temperature from room temperature to 125oC for from 30 min to 48 h to obtain the compounds of formula V. Suitable bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, potassium fluoride, and barium hydroxide. Suitable palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)-palladium(II), palladium(II) acetate dimer allylpalladium chloride and Tris(dibenzylideneacetone)dipalladium(0). The reaction medium may also contain optional three(C6-C10)arylphosphine or three(C1-C6)alkylphosphine, examples of which include, but are not limited to, triphenylphosphine, tri-tert-butylphosphine and tri-o-tolylphosphino. Suitable inert solvents for the reaction include, but are not limited to, tetrahydrofuran, toluene, dioxane, dimethoxyethane, ethanol, dimethylformamide and dimethylacetamide, optionally containing water. For example, in one embodiment, the stage 2 scheme 1 cluever catalyst tetrakis(triphenylphosphine)palladium(0) in a mixture of toluene, ethanol and water at a temperature of about 100oC for about 8 hours

Stage 3 scheme 1 involves removing protection in connection V. In particular, acylated aniline compounds V interacts with the aqueous acid solution for from 1 to 48 hours at a temperature of from room temperature to the boiling temperature to obtain a salt of 2-phenyl-3-aminopyridine (compound VI). Suitable acids include, but are not limited to, hydrochloric acid, Hydrobromic acid, sulfuric acid and triperoxonane acid. For example, in one embodiment, the stage 3 is carried out in hydrochloric acid at the boiling temperature for 14 h to obtain the hydrochloride of 2-phenyl-3-aminopyridine.

Stage 1 scheme 2 involves the formation of imine. Aniline compound of formula I is treated with an aldehyde of formula VII in an inert solvent reaction using a dehydrating agent or apparatus at a temperature of from room temperature to the boiling temperature for 4 to 48 h to obtain the compounds of formula VIII. Suitable inert solvents for the reaction include, but are not limited to, toluene, xylene, tetrahydrofuran, heptane, dioxane and dimethoxyethane. Suitable dehydrating agents include, but are not limited to the and. For example, in one embodiment, the compound of formula I interacts with the compound of the formula VII in toluene for about 18 hours using the apparatus of Dean-stark to obtain the compounds of formula VIII.

Stage 2 in scheme 2 involves the reaction of a combination of Suzuki compounds of formula VIII with a compound of formula IV to obtain 2-phenyl-3-aminopyridine (formula IX). In particular, the compound of formula VIII is treated with a compound of formula IV in an inert solvent to the reaction, optionally containing water, in the presence of a base and a palladium catalyst at a temperature from room temperature to 125oC for from 10 min to 24 h to obtain 2-phenyl-3-aminopyridine (formula IX). Suitable bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, and barium hydroxide. Suitable palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium(0), dichloro-bis(triphenylphosphine)palladium(II), palladium(II) acetate dimer allylpalladium chloride and Tris(dibenzylideneacetone)dipalladium(0). The reaction medium may also contain optional three (C6-C10) arylphosphine or three (C1-C6) alkylphosphine, PR is ing solvents include, but not limited to, tetrahydrofuran, toluene, dioxane, dimethoxyethane, ethanol, dimethylformamide and dimethylacetamide. For example, in one embodiment, the compound of formula VIII interacts with phenylboronic acid in the presence of sodium carbonate and tetrakis(triphenylphosphine)palladium(0) in a mixture of toluene and water at a temperature of about 100oC for 30 min to obtain 2-phenyl-3-aminopyridine.

The circuit 3 includes a variant of the method of the present invention, similar to the method of scheme 2, but which flows through the protection of in situ aniline compounds of formula I, i.e. the stage of the formation of a secure connection and combination of this compound with a phenyl group, such as stage 1 and 2 schema 2 occur essentially simultaneously. Specifically, in scheme 3, the compound I is treated with an aldehyde of the formula VII and a compound of formula IV in an inert solvent to the reaction in the presence of a base and a palladium catalyst at a temperature from room temperature to 125oC for from 10 min to 48 h to obtain 2-phenyl-3-aminopyridine (formula IX). Suitable bases include, but are not limited to, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide and barium hydroxide. Suitable PA) dichlorobis(triphenylphosphine)palladium(II) dimer allylpalladium chloride and Tris(dibenzylideneacetone)dipalladium(0). The reaction medium may also contain optional three(C6-C10)arylphosphine or three(C1-C6)alkylphosphine, examples of which include, but are not limited to, triphenylphosphine, tri-tert-butylphosphine and tri-o-tolylphosphino. Suitable solvents include, but are not limited to, toluene, tetrahydrofuran, dioxane, dimethoxyethane, ethanol, dimethylformamide and dimethylacetamide. The reaction medium may also contain water. For example, in one embodiment, the compound of formula I is treated with a compound of the formula VII and phenylboronic acid in the presence of sodium hydroxide and palladium(II) acetate and triphenylphosphine in a mixture of toluene and water at a temperature of about 100oC for about 18 h to obtain 2-phenyl-3-aminopyridine.

Derivatives of 2-phenyl-3-aminopyridine, where the phenyl group is substituted by Z, as defined above, and Z is other than H, get, using a corresponding compound of formula

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instead of the PhB(OR3)(OR4) shown in the reaction schemes.

2-Phenyl-3-aminopyridine can be turned into antagonists of substance P in the following ways, operaista R capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, often in practice it is preferable to select the primary connection from the reaction mixture in the form of a pharmaceutically unacceptable salt and then turn it into a free base by treatment with an alkaline reagent and subsequently convert the free base in pharmaceutically acceptable acid additive salt. An acid additive salt is easily obtained by processing the primary connection, essentially, equivalent to the number of selected inorganic or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. After evaporation of the solvent to obtain the desired solid salt. Acid, which are used to produce pharmaceutically acceptable acid additive salts of the basic compounds are those that form non-toxic acid additive salts, i.e. salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, meoac)).

Antagonists of substance P obtained using 2-phenyl-3-aminopyridine as an intermediate product, show significant binding activity against receptor for substance P and, therefore, are valuable for the treatment of a wide variety of clinical conditions which are characterized by increased activity of substance P. Such conditions include, but are not limited to, cardiovascular diseases, allergic diseases, angiogenesis, gastrointestinal diseases, diseases of the Central nervous system, inflammatory diseases, vomiting, incontinence, pain, migraine, severe disease with the phenomenon of fear, stress disorder, the fear expressed depressive disorders expressed depressive disorders, which accompanies a state of fear, depression, sunburn, sexual dysfunction, bipolar disorders, abuse of drugs, schizophrenia, disorders of motor activity, disorders of cognitive abilities and diseases, disorders and the side effects caused by Helicobacter pylori in mammals, especially in humans. For the treatment of vomiting, these compounds can be used in combination with an antagonist NT3-receptors.

sterelny (for example, intravenous, intramuscular or subcutaneous) routes or externally. In General, these compounds are most preferably administered to humans in doses ranging from 0.3 to 750 mg per day, although will take place changes depending on the weight and condition of the subject being treated and the particular route of administration. However, the most desirable dose in the range from 0.06 to 6 mg per 1 kg of body weight.

Antagonists of substance P can be introduced as such or in combination with pharmaceutically acceptable carriers or diluents by any of the ways described above, in the form of one or more doses. Thus, antagonists of substance P can be introduced in the form of a wide variety of dosage forms, including tablets, capsules, wafers, cakes, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs and syrups. Suitable pharmaceutically acceptable carriers for use in such dosage forms include solid diluents or fillers, sterile aqueous medium and various non-toxic organic solvents. Pharmaceutical compositions for oral administration can, respectively, sweeten and is in the range of 5 to 70% by mass.

For oral administration can be used tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, along with various loosening substances such as starch (and preferably corn, potato or manioc starch), alginic acid and certain complex silicates, together with binding agents for granulation, such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum. In addition, for tabletting, you can use lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Such compositions can be used as fillers in gelatin capsules; preferred substances include lactose or milk sugar and high molecular weight glycols. When oral administration is desirable aqueous suspensions and/or elixirs, the active ingredient can be combined with various sweetening or flavoring agents, tinted substance or dyes and, if desired, emulsifiers and/or suspendresume substance together with diluents, such as water, ethanol, propylene glycol and glycerin.

For new oil or in aqueous propylene glycol. Aqueous solutions, if necessary, accordingly, to tabularity (preferably, pH>8) and the first liquid diluent to make isotonic. Such aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The preparation of these solutions under sterile conditions is easy to implement using standard pharmaceutical techniques.

The present invention is illustrated by the following examples, but is not limited to them.

Example 1. N-(2-Chloro-pyridine-3-yl)-ndimethylacetamide

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To a solution of 2-chloro-3-aminopyridine (51,4 g, 400 mmol) in dichloromethane (800 ml) at 0oWith the added triethylamine (31,0 ml, 440 mmol), then acetylchloride (62,0 ml, 440 mmol). The reaction mixture is allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured into water (800 ml) and the layers were separated. The organic layer was treated with DarcoTM-G-60 activated carbon) was boiled under reflux, filtered through CeliteTM(diatomaceous earth, manufactured by Celite Corp., Santa Barbara, CA) and concentrated to oil. The oil was led from diisopropyl ether and the solids were filtered to obtain 42,4 g (62%) in order. with a, 1), of 8.06 (DD, 1, J=4,7, 1,3), 8,66 (DD, 1, J= 4,7, 1,3).13With NMR (100 MHz, D13) 24,93, 123,34, 129,06, 131,89, 143,81, 144,08, 168,79.

Example 2. N-(2-Phenyl-pyridin-3-yl)-ndimethylacetamide hydrochloride

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To a mixture of N-(2-chloro-pyridine-3-yl)-ndimethylacetamide (50.0 g, of 29.3 mmol), phenylboronic acid (39,3 g is 32.2 mmol), sodium carbonate (49,7 g, 46,9 mmol) in toluene (400 ml), ethanol (100 ml) and water (200 ml) was added tetrakis(triphenylphosphine)palladium(0) (1,02 g, 0,883 mmol). The reaction mixture is boiled under reflux for 8 h, cooled to room temperature and the layers were separated. The aqueous layer was extracted with ethyl acetate (500 ml) and the organic extracts were combined and concentrated to a yellow solid. The crude solid was dissolved in methanol (500 ml) and added concentrated hydrochloric acid (10 ml). The solution was concentrated to small volume and added tetrahydrofuran (500 ml). The solid was washed, filtered and dried to obtain N-(2-phenyl-pyridin-3-yl)-ndimethylacetamide hydrochloride (62.5 g, 86%). So pl.=262-263oS.1H NMR (300 MHz, DMSOd6) 2,52 (s, 3), 6,30 (Shir. C, 2), of 7.64-7,72 (m, 6), 7,78 (DD, 1, J=1,2, 8,6), of 8.06 (DD, 1, J=1,2, 5,2).

Example 3. 2-Phenyl-3-aminopyridine hydrochloride

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To a solution of N-(2-phenyl-pyridin-3-yl)-ndimethylacetamide hydrochloride (61,9 g, Il under reflux overnight and then concentrated to small volume. Added tetrahydrofuran (2000 ml) and the volume reduced to approximately 1000 ml prior to the deposition of the product. The mixture was cooled to 0oC and stirred for 2 hours the Solids were filtered to obtain 2-phenyl-3-aminopyridine hydrochloride (46.2 g, 90%). So pl.= 226-227 of theoS.1H NMR (300 MHz, D13) 6,35 (Shir. C, 3), to 7.61-7,74 (m, 6), of 7.82 (DD, 1, J=1,4, 8,6), with 8.05 (DD, 1, J=1,5, 5,4). Data analysis, calculated for C11H11CIN2: C, 63,93; N, ARE 5.36; N, 13,55. Found: C, 63,64; N, 5,20; N, 13,49.

Example 4. 2-Phenyl-3-aminopyridine

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To 2-chloro-3-aminopyridine (1.06 g, 8,24 mmol) in toluene (25 ml) was added benzaldehyde (of 0.878 g of 8.27 mmol). The reaction mixture was stirred while boiling under reflux in an apparatus of the Dean-stark before until analysis of the reaction mixture GC/MS showed no more than the existence of the original substance. The reaction mixture was cooled to room temperature and was added to the solution of benzylidene-(2-chloro-pyridine-3-yl)-amine in toluene to a mixture of phenylboronic acid (1.30 grams, of 10.7 mmol), sodium carbonate (2.66 g, a 25.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.38 mol%) in water (10 ml). The reaction mixture was heated to 100oC for 30 min, cooled to room temperature and poured into 1 N. aqueous solution of sodium hydroxide (10 ml). The aqueous layer was neutralized to pH 12 6 N. aqueous solution of sodium hydroxide and was extracted with MTBE (twice 20 ml). MTBE extracts were dried over magnesium sulfate, was filtered and was concentrated to obtain 2-phenyl-3-aminopyridine in the form of a solid substance, which was led from diisopropyl ester (1.26 g, yield 90%). So pl.= 67-68oS.1H NMR (300 MHz, CDCl3) 3,88 (Shir. C, 2), 7,02-7,11 (m, 2), 7,28-7,53 (m, 3), to 7.67-7,71 (m, 2), 8,13-8,16 (m, 1).13With NMR (100 MHz, D13) 122,57, 122,96, 128,14, 128,38, 128,72, 138,54, 139,86, 139,93, 144,93.

Example 5. 2-Phenyl-3-aminopyridine

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A solution of palladium acetate (224,5 g, 1.00 mmol) and triphenylphosphine (of 1.05 g, 4.00 mmol) in toluene (1000 ml) was stirred at room temperature for 15 minutes Then added phenylboronic acid (114 g, 935 mmol), 2-chloro-3-aminopyridine (100 g, 778 mmol), benzaldehyde (of 83.4 g, 786 mmol) and toluene (500 ml) followed by the addition of sodium carbonate solution (200 g, 1,89 mol) in water (1500 ml). The mixture was boiled under reflux for 18 h, cooled to room temperature and the layers were separated. The organic layer was washed with water (500 ml), and added a 2.5 M aqueous solution of hydrochloric acid (630 ml). The aqueous layer was separated and washed with toluene (300 ml), the pH is brought up to 12-13 using 50% aqueous sodium hydroxide solution, and the mixture ekstragirovanija ether to obtain 2-phenyl-3-aminopyridine (128 g, yield 97%). So pl.=67-68oS.1H NMR (300 MHz, CDCl3) 3,88 (Shir. C, 2), 7,02-7,11 (m, 2), 7,28-7,53 (m, 3), to 7.67-7,71 (m, 2), 8,13-8,16 (m, 1). 13With NMR (100 MHz, CDCl3) 122,57, 122,96, 128,14, 128,38, 128,72, 138,54, 139,86, 139,93, 144,93.

1. The method of obtaining 2-phenyl-3-aminopyridine or substituted phenyl derivatives suitable for the production of salts of 2-phenyl-3-aminopyridine or substituted phenyl compounds, including interaction of the compounds of formula VIII

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with the compound of the formula IV

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in an inert solvent to the reaction in the presence of a base and palladium catalyst to obtain the compounds of formula X

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where X is C1, Br or I;

Z is H, (C1-C4) alkyl, methoxy, triptoreline, F or C1;

AG is a (C6-C10) aryl, optionally substituted by 1 to 3 groups of R5;

R3and R4independently selected from H and (C1-C6) alkyl, where, when R3and R4are (C1-C6) alkyl, they may be condensed together with the formation of a ring structure;

R5each independently selected from halogen, cyano, nitro, (C1-C6)-of halogensubstituted alkyl, (C1-C6)alkoxy, (C6-C10)aryloxy, (C1-C61-C6)alkylthio, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonyl,(C1-C6)alkyl-OC(O)-,(C1-C6)alkyl-OC(O)-(C1-C6)alkyl, (C1-C6)alkyl-C(O)O-, (C1-C6)alkyl-C(O)-(C1-C6)alkyl-O-, (C1-C6)alkyl-C(O)-, (C1-C6)alkyl-C(O)-(C1-C6)alkyl, (C6-C10)aryl-, (C6-C10)aryl-(C1-C6)alkyl - (C3-C7)cycloalkyl, where one or two carbon atoms of the specified cycloalkyl may be optionally substituted by a nitrogen atom, oxygen or sulfur.

2. The method according to p. 1, further comprising obtaining the compounds of formula VIII by the interaction of the compounds of formula

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with the compound of the formula VII

AgSnO,

in an inert solvent reaction where the specified reaction of compound VIII with a compound IV occurs essentially simultaneously with or after the specified reaction of compound I with compound VII.

3. The method according to p. 2, where Z is H, R3and R4- N, and each R5independently selected from normal or branched (C1-C6)alkyl, phenyl, benzyl, trifloromethyl, (C1-C6)alkoxy, triptoreline.


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with the compound of the formula IV

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in an inert solvent to the reaction in the presence of a base and palladium catalyst to obtain the compounds of formula V

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where X Is CL, Br or I;

Z - N, (C1-C4) alkyl, methoxy, triptoreline, F or C1;

R1is a normal or branched (C1-C6)alkyl, (C3-C7)cycloalkyl or (C6-C10)aryl, and these alkyl, cycloalkyl and aryl optionally substituted by 1 to 3 groups of R5;

R3and R4independently selected from H and (C1-C6) alkyl, where, when R3and R4are (C1-C6)alkyl, they may be condensed together with the formation of a ring structure;

R5each independently selected from halogen, cyano, nitro, (C1-C6)-of halogensubstituted alkyl, (C1-C6)alkoxy, (C6-C10)aryloxy, (C1-C6)-halogen-substituted alkoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C1-C6)alkylthio, (C1-C61-C6)alkyl, (C1-C6)alkyl-C(O)O-, (C1-C6)alkyl-C(O)-(C1-C6)alkyl-O-, (C1-C6)alkyl-C(O)-, (C1-C6)alkyl-C(O)-(C1-C6)alkyl, (C6-C10)aryl-, (C6-C10)aryl-(C1-C6)alkyl - (C3-C7)cycloalkyl, where one or two carbon atoms of the specified cycloalkyl may be optionally substituted by a nitrogen atom, oxygen or sulfur.

6. The method according to p. 5, further comprising obtaining the compounds of formula III by the interaction of the compounds of formula I

< / BR>
with the compound of the formula II

< / BR>
in an inert solvent reaction

where Y Is CL, Br, I or-OC(O)R2;

R2is a normal or branched (C1-C6)alkyl, (C3-C7)cycloalkyl or (C6-C10)aryl, and these alkyl, cycloalkyl and aryl optionally substituted by 1 to 3 groups of R5where the specified reaction of compound III with compound IV occurs essentially simultaneously with or after the specified reaction of compound I with compound II.

7. The method according to p. 5, where the compound of formula V get this way, additionally comprising removing the protection from the compounds of formula V in water OC the same and are independently chosen from a normal or branched (C1-C6)alkyl and phenyl, where these R1and R2optionally substituted by 1 to 3 R5groups; R3and R4- N, and each R5independently selected from normal or branched (C1-C6)alkyl, phenyl, benzyl, trifloromethyl, (C1-C6)alkoxy, triptoreline.

9. The method according to p. 6, where R1and R2is methyl.

10. The method according to p. 6, where R1is stands and R2- tert-bootrom.

11. The method according to p. 6, where X Is CL and Y is CL.

12. The method of obtaining 2-phenyl-3-aminopyridine, including (a) the interaction of the compounds of formula I

< / BR>
with the compound of the formula VII

AgSnO

in an inert solvent reaction with obtaining the compounds of formula VIII

< / BR>
and (b) the interaction of the compounds of formula VIII with the compound of the formula IV

< / BR>
in an inert solvent to the reaction in the presence of a base and palladium catalyst to obtain the compounds of formula X

< / BR>
where X Is CL, Br or I;

Z is H, (C1-C4) alkyl, methoxy, triptoreline, F or CL;

AG - (C6-C10) aryl, optionally substituted by 1 to 3 R5groups;

R3and R4independently selected from H and (C1-C6) AE with the formation of a ring structure;

R5each independently selected from halogen, cyano, nitro, (C1-C6)-of halogensubstituted alkyl, (C1-C6)alkoxy, (C6-C10)aryloxy, (C1-C6)-halogen-substituted alkoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkyl-OC(O)-, (C1-C6)alkyl-OC(O) - (C1-C6)alkyl, (C1-C6) alkyl-C(O)O-, (C1-C6)alkyl-C(O)-(C1-C6) alkyl-O-,

(C1-C6)alkyl-C(O)-, (C1-C6) alkyl-C(O)-(C1-C6)alkyl, (C6-C10)aryl-,

(C6-C10)aryl-(C1-C6)alkyl - and (C3-C7)cycloalkyl, where one or two carbon atoms of the specified cycloalkyl may be optionally substituted by a nitrogen atom, oxygen or sulfur.

13. The method according to p. 12, where the stage (a) and (b) are conducted essentially simultaneously.

14. The method according to p. 12, where Z Is H, R3and R4- N, and each R5independently selected from normal or branched (C1-C6)alkyl, phenyl, benzyl, trifloromethyl, (C1-C6)hunger.

 

Same patents:

The invention relates to new derivatives of carbamino acid of General formula 1, where R1and R2independently of one another denote alkyl, aryl, aralkyl, heteroaryl, cycloalkyl or heterocyclyl, R3and R4independently of one another denote hydrogen, alkyl, halogen, hydroxyl or aryl, R5means-COOR6, R6denotes hydrogen or alkyl, And indicates alkylen or albaniles, denotes-O(CH2)m- or -(CH2)n-, m denotes an integer from 1 to 8, inclusive, n represents an integer from 0 to 8, inclusive, or their racemates, or individual isomers, or their new pharmaceutically acceptable salt, or solvate

The invention relates to new derivatives of aryl - and heteroarylboronic General formula I, where R1denotes a substituted phenyl or pyridyl, R2denotes a substituted phenyl, R3denotes hydrogen, (lower)alkyl, cyano, carboxy, esterified carboxylate, phenyl, 1H-tetrazolyl or the group,- CONR5R6, R5denotes hydrogen or the radical R7, R6represents -(CH2)mR7or R5and R6together with the nitrogen atom to which they are attached, denote morpholino, 2,6-dimethylmorpholine, piperidino, 4-(lower)alkylpiperazine, 4-(lower)alkoxyimino, 4-(lower)alkoxycarbonylmethyl or 4 formylpiperazine,7denotes phenyl, substituted phenyl, pyridyl, 1H-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl or phenyl(lower)alkoxycarbonyl, Radenotes hydrogen or hydroxy, Rbrepresents hydrogen, Z represents hydroxy or the group-OR8or-OC(O)NR8, R8denotes pyridyl or pyrimidinyl, X represents nitrogen or CH, m is 0, 1 or 2, n is 0, 1 or 2, and

The invention relates to a series of compounds, their pharmaceutically acceptable salts and their N-oxides, a process for the production of the above-mentioned compounds, salts or N-oxides, to pharmaceutical preparations containing the said compounds, dosage units of drugs and to methods of treating patients using the mentioned preparations and dosage units

The invention relates to therapeutically active hydroxamic acids and derivatives of carboxylic acids, processes for their preparation, to pharmaceutical compositions containing these compounds and to the use of such compounds in medicine

The invention relates to new derivatives of salicylic acid f-ly Gets-NR-SO2-Ph1A Ph2(COOH)(OH), (I), where Het represents (R1, R2, R3-Het1That gets1represents a cyclic systemin which the free valence is associated with a group NR; X is a group: a) -O-CH=CH-, -CH=CH-O-, -CH= CH-S - or b) -CH=CH-CH=CH-, -CH=CH-CH=N-, -CH=N-CH=CH-, -CH=CH-N=CH-, -N= CH-CH= CH-; R1, R2and R3are substituents at the carbon atom in Het and represent hydrogen, C1-C6- alkyl, halogen, hydroxy - or benzyloxy; R is hydrogen or C1-C6- alkyl; Ph1- phenylene, Ph2is phenyl which may be substituted with halogen, lower alkyl or benzyloxypropionic, provided that the carboxy - and hydroxy-group are in the ortho-position to each other; And a represents - CC-, -CH=CH-, -CH2-CH2-, -CO-CH=CH-, -CH=CH-CO-

The invention relates to a new method of obtaining the known anticancer means, more specifically, to a method for producing (S)-(-)- and (R)-(+)-isomers of complex ethyl ester (5-amino-1,2 - dihydro-2-methyl-3-phenylperhydro-[3,4-b] pyrazin-7-yl)urea acid or their pharmaceutically acceptable salts, as well as to new intermediate (S)-(-)- and (R)-(+)-isomers of complex ethyl ester [6-amino-4-[[2-(alkoxyalkyl-amino)-1 - methyl-2-oxoethyl] amino]-5-nitro-2-pyridinyl]urea acid, which is used in this way

The invention relates to new derivatives of diaminodiphenylmethane or their salts and process for their preparation, to the inhibitor of phospholipase A2, an anti-inflammatory agent and protivopsoriaticescoe agent containing them, as well as to new derivatives of triptoreline as intermediate products

The invention relates to a new derived pyridonecarboxylic acid of the formula I or salts thereof, which possess high antibacterial activity and can find application in medicine

The invention relates to new amino compounds to obtain new derivatives pyridonecarboxylic acids or their salts having excellent antibacterial properties and oral absorption and is used as antibacterial agents

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing inhibitory effect on activity of dipeptidyl peptidase IV (DPP IV) that can be used, for example, in treatment of diabetes mellitus type 2. In compounds of the formula (I) X means nitrogen atom (N) or -C-R5; R1 and R2 mean independently hydrogen atom, (C1-C6)-alkyl; R3 means saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, or perfluoro-(C1-C6)-alkyl; R4 means (lower)-alkyl, (lower)-alkoxy-, (lower)-alkylthio-group, saturated or aromatic 7-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-, amino-group or perfluoro-(C1-C6)-alkyl, 4-fluorophenyloxy-(C1-C6)-alkyl or (C3-C6)-cycloalkyl; R5 means hydrogen atom or (C1-C6)-alkyl. Also, invention relates to methods for synthesis of compounds of the formula (I), pharmaceutical compositions and their using for preparing medicaments used in treatment and/or prophylaxis of DPP IV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

21 cl, 93 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein radicals and symbols have values given in the invention claim. Compounds of the formula (I) possess properties of H3 receptors antagonist. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I). Also, invention relates to a method for treatment of disease of group comprising difficulty in nasal breath, obesity, somnolence, narcolepsy, attention deficiency with hyperactivity, Alzheimer's disease and schizophrenia that involves using compounds of the formula (I) and, optionally, in combination of H receptor antagonist.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

39 cl, 3 tbl, 31 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of aniline of the general formula (I): and their pharmaceutically acceptable salts and isomeric forms possessing properties of phosphodiesterase-4 inhibitors. Compounds can be used, fore example, for enhancing cognitive ability. In compounds of the general formula (I) R1 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more halogen atoms; R2 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkoxy or their combinations, (C3-C10)-cycloalkyl, (C4-C16)-cycloalkylalkyl wherein alkyl fragment comprises from 1 to 4 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and alkyl fragment that can be linear or branched and comprises from 1 to 5 carbon atoms and wherein radical arylalkyl can be unsubstituted or substituted in aryl fragment with one or more substitutes of the following order: halogen atom, alkoxy group comprising from 1 to 4 carbon atoms or their combinations, and in alkyl fragment one group -CH2CH2- is optionally replaced for group -CH=CH-, and one group -CH2- is optionally replaced for -O- for -NH-, partially unsaturated carbocyclic group comprising from 5 to 9 carbon atoms that can comprise condensed benzene ring, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including one atom chosen from oxygen (O), or heterocyclylalkyl group wherein heterocyclic fragment can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including 1-2 atoms chosen from nitrogen (N) or sulfur (S) atoms, and alkyl fragment that can be linear or branched comprises from 1 to 5 carbon atoms; R3 means partially unsaturated carbocyclylalkyl group wherein carbocyclic fragment comprises from 5 to 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein arylalkyl radical can be linear or substituted in aryl fragment with one or more substitutes of the following group: trifluoromethyl, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations, heterocyclylalkyl group wherein heterocyclic fragment can be aromatic, partially or completely saturated and comprises from 5 to 10 atoms in cycle including 1-2 atoms chosen from N, O or S, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein heterocyclylalkyl group can be linear or substituted in heterocyclic fragment with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations; R4 means (C6-C12)-aryl that can be linear or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C2-C4)-alkenyl, hydroxy, (C1-C4)-alkoxy, (C2-C4)-alkoxyalkoxy, nitro, trifluoromethyl, -OCF3, amino group, aminoalkyl, aminoalkoxy, hydroxy-(C1-C4)-alkyl, hydroxamic acid, tetrazol-5-yl, 2-(heterocyclyl)-tetrazol-5-yl, carboxy, alkoxycarbonyl, cyano, acyl, alkylsulfonyl, phenoxy, trialkyloxy, R5-L or their combinations, or heteroaryl comprising from 5 to 10 atoms in cycle including 1-2 atoms chosen from N wherein heteroaryl can be linear or substituted with one or more substitutes of the following order: (C1-C4)-alkyl, (C1-C4)-alkoxy, carboxy, alkoxycarbonyl or their combinations; R5 means hydrogen atom, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, C6-aryl, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 10 atoms in cycle from which at least atom means N or O, and wherein heterocyclic group can be linear or substituted with one or more (C1-C4)-alkyls, or group heterocyclylalkyl, and others. Also, invention relates to intermediates compounds and to a method for enhancing the cognitive ability.

EFFECT: valuable biological and biochemical property of compounds.

49 cl, 8 sch, 26 ex

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